Two popular but still untested hypotheses explaining contractile dysfunction in heart failure are 1) a mismatch between energy supply and demand and 2) abnormalities in excitation-contraction (E-C) coupling due to Ca availability and/or mobilization. The advantage of using an animal model to study heart failure is that the applicants are able to perform a longitudinal study, thereby focusing on pathogenesis of the heart disease without pharmacologic intervention. Utilizing an animal model of heart failure (furazolidone-induced, Fz-DCM), the applicants have already found that both failing human and turkey myocardium undergo similar changes with regard to specific receptors and enzymes that are important for E-C coupling and energetics. Applicant's studies acquire the use of a multifaceted experimental approach. The need to bring together expertise in several areas to study this complex disease affecting multiple intracellular events motivates this multidisciplinary collaborative proposal. Specific Aim 1: Will define the relationships among Ca i, Ca mobilization and contractile dysfunction in heart failure, by testing the hypothesis that changes in Ca2+ mobilization alter contractility. Specific Aim 2: will be to define the relationship between energy reserve and contractile reserve in an animal model of human heart failure. Hypothesis: (1) is that prolonged inhibition of energy reserve caused by either decreasing creatine kinase activity or decreasing guanidino substrate results in or exacerbates dilated cardiomyopathy and (2) that a mechanistic relationship exists between energy reserve and cardiac dysfunction; hearts with compensated heart disease when stressed by increased work and/or further decreases in energy supply will demonstrate decompensation and contractile failure as a result of a mismatch between energy supply and demand.